(5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone -Drug Synthesis Database

【结构式】

【分子编号】40830

【品名】(5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone

【CA登记号】

【分子式】C₂₁H₄₆O₃Si₂

【分子量】402.76544

【元素组成】C 62.62% H 11.51% O 11.92% Si 13.95%

与该中间体有关的原料药合成路线共 9 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6 合成路线7 合成路线8 合成路线9

合成路线1

该中间体在本合成路线中的序号：(XIX)

The silylation of 3(S)-hydroxytetrahydrofuran-2-one (I) with TBDMS-Cl and imidazole gives the silyl ether (II), which is methylated with MeLi in THF yields the 3(S)-(TBDMSO)-5-hydroxy-2-pentanone (IV), through the hemiketal intermediate (III). Simultaneously, the cyclization of 1,3-dichloropropanone (V) with thioacetamide (VI) in refluxing ethanol affords 4-(chloromethyl)-2-methylthiazole (VII), which is treated with tributylphosphine to provide the phosphonium salt (VIII). The condensation of (VIII) with the ketone (IV) gives the unsaturated alcohol (IX), which is oxidized to the corresponding aldehyde (X) by means of oxalyl chloride in DMSO. The condensation of (X) with 2-phosphonopropionic acid triethyl ester (XI) by means of KHMDS gives the dienoic acid ethyl ester (XII), which is reduced with DIBAL in THF yielding the corresponding primary alcohol (XIII). The condensation of (XIII) with the chiral sulfone intermediate (XIV) by means of KHMDS and PPh3 affords the corresponding adduct (XV), which is desulfurized with Na/Hg in THF/methanol giving the silylated diol (XVI). The selective monodesilylation of (XVI) with CSA in methanol/dichloromethane yields the primary alcohol (XVII), which is oxidized with Dess Martin periodinane (DMP) to the aldehyde (XVIII). The condensation of (XVIII) with the intermediate chiral ketone (XIX) by means of LDA in THF affords the hydroxy ketone (XX).

参考文献中间体

合成目标

【1】 Mulzer, J.; Ohler, E.; Mantoulidis, A. (Schering AG); Method for producing epothilone B and derivs., and intermediate products for this method. WO 0023452 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	40815	(3S)-3-hydroxydihydro-2(3H)-furanone	19444-84-9	C₄H₆O₃	详情	详情
(II)	40816	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]dihydro-2(3H)-furanone		C₁₀H₂₀O₃Si	详情	详情
(III)	40817	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyltetrahydro-2-furanol		C₁₁H₂₄O₃Si	详情	详情
(IV)	40818	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-2-pentanone		C₁₁H₂₄O₃Si	详情	详情
(V)	63907	1,3-dichloroacetone		C₃H₄Cl₂O	详情	详情
(VI)	19170	ethanethioamide	62-55-5	C₂H₅NS	详情	详情
(VII)	40819	4-(chloromethyl)-2-methyl-1,3-thiazole		C₅H₆ClNS	详情	详情
(VIII)	40820	tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride		C₁₇H₃₃ClNPS	详情	详情
(IX)	40821	(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol		C₁₆H₂₉NO₂SSi	详情	详情
(X)	40822	(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal		C₁₆H₂₇NO₂SSi	详情	详情
(XI)	18816	ethyl 2-(diethoxyphosphoryl)propanoate	3699-66-9	C₉H₁₉O₅P	详情	详情
(XII)	40823	ethyl (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienoate		C₂₁H₃₅NO₃SSi	详情	详情
(XIII)	40824	(2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol		C₁₉H₃₃NO₂SSi	详情	详情
(XIV)	40825	tert-butyl(dimethyl)[[(2S)-2-methyl-4-(phenylsulfonyl)butyl]oxy]silane; (3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methylbutyl phenyl sulfone		C₁₇H₃₀O₃SSi	详情	详情
(XV)	40826	(1R,3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-1-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl phenyl sulfone; 4-[(1E,3S,5Z,8R,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-8-(phenylsulfonyl)-1,5-undecadienyl]-2-methyl-1,3-thiazole		C₃₆H₆₁NO₄S₂Si₂	详情	详情
(XVI)	40827	tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole		C₃₀H₅₇NO₂SSi₂	详情	详情
(XVII)	40828	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol		C₂₄H₄₃NO₂SSi	详情	详情
(XVIII)	40829	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal		C₂₄H₄₁NO₂SSi	详情	详情
(XIX)	40830	(5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone		C₂₁H₄₆O₃Si₂	详情	详情
(XX)	40831	(7S,10R,11S,12S,16Z,19S)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one		C₄₅H₈₇NO₅SSi₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIX)

The intermediate chiral ketone (XIX) has been obtained as follows: The silylation of 3(S)-hydroxy-2,2-dimethyl-5-(TBDMSO)pentanoic acid methyl ester (XXXIV) with TBDMS-triflate gives the fully silylated ester (XXXV), which is reduced with DIBAL in THF to yield the alcohol (XXXVI). The oxidation of (XXXVI) with Dess Martin periodinane (DMP) affords the aldehyde (XXXVII), which by reaction with ethylmagnesium bromide in ethyl ether provides the expected secondary alcohol (XXXVIII). Finally, this compound is oxidized with Dess Martin periodinane (DMP) to furnish the target chiral ketone (XIX).

参考文献中间体

合成目标

【1】 Mulzer, J.; Ohler, E.; Mantoulidis, A. (Schering AG); Method for producing epothilone B and derivs., and intermediate products for this method. WO 0023452 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIX)	40830	(5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone	C₂₁H₄₆O₃Si₂	详情	详情
(XXXIV)	40843	methyl (3S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-2,2-dimethylpentanoate	C₁₄H₃₀O₄Si	详情	详情
(XXXV)	40844	methyl (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethylpentanoate	C₂₀H₄₄O₄Si₂	详情	详情
(XXXVI)	40845	(3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethyl-1-pentanol	C₁₉H₄₄O₃Si₂	详情	详情
(XXXVII)	40846	(3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethylpentanal	C₁₉H₄₂O₃Si₂	详情	详情
(XXXVIII)	40847	(5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanol	C₂₁H₄₈O₃Si₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XXVII)

The enantioselective condensation of 3-(tert-butyldimethylsilyloxy)propanal (XX) with ketene acetal (XXI) catalyzed by N-tosyl-D-valine and BH3/THF gives the beta-hydroxyester (XXII), which is silylated with Tbdms-OTf, yielding the bis-silyl ether (XXIII). The reduction of (XXIII) with DIBAL in toluene affords the carbinol (XXIV), which is oxidized to the corresponding aldehyde (XXV) with DMP in dichloromethane. The Grignard condensation of (XXV) with Et-MgBr in ethyl ether gives the secondary alcohol (XXVI), which is oxidized with DMP as before to yield the ketone (XXVII). Alternatively, the silylated ester (XXIII) can be treated with Tms-CH2-Li in pentane/methanol to give the methyl ketone (XXVIII), which is methylated again with MeI and LDA in THF to afford the ketone (XXVII). The condensation of ketone (XXVII) with the intermediate carbaldehyde (XIX) by means of BuLi in THF gives the adduct (XXIX), which is silylated with Tbdms-OTf, yielding the fully silylated compound (XXX). The selective monodesilylation of (XXX) with CSA in MeOH/dichloromethane affords the primary alcohol (XXXI), which is oxidized with DMP and NaClO2 to provide the carboxylic acid (XXXII).

参考文献中间体

合成目标

【1】 Mulzer, J.; et al.; Total synthesis of epothilones B and D. J Org Chem 2000, 65, 22, 7456.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIX)	40829	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal		C₂₄H₄₁NO₂SSi	详情	详情
(XX)	45546	3-[[tert-butyl(dimethyl)silyl]oxy]propanal	570-24-1	C₉H₂₀O₂Si	详情	详情
(XXI)	42016	1-Methoxy-2-methyl-1-(trimethylsiloxy)propene;1-Methoxy-2,2-dimethyl-1-(trimethylsiloxy)ethene;1-Methoxy-1-(trimethylsilyloxy)-2-methylpropene;[(1-methoxy-2-methyl-1-propenyl)oxy](trimethyl)silane; 1-methoxy-2-methyl-1-propenyl trimethylsilyl ether ;dimethylketene methyl trimethylsilyl acetal	31469-15-5	C₈H₁₈O₂Si	详情	详情
(XXII)	40843	methyl (3S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-2,2-dimethylpentanoate		C₁₄H₃₀O₄Si	详情	详情
(XXIII)	40844	methyl (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethylpentanoate		C₂₀H₄₄O₄Si₂	详情	详情
(XXIV)	40845	(3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethyl-1-pentanol		C₁₉H₄₄O₃Si₂	详情	详情
(XXV)	40846	(3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethylpentanal		C₁₉H₄₂O₃Si₂	详情	详情
(XXVI)	40847	(5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanol		C₂₁H₄₈O₃Si₂	详情	详情
(XXVII)	40830	(5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone		C₂₁H₄₆O₃Si₂	详情	详情
(XXVIII)	46137	(4S)-4,6-bis[[tert-butyl(dimethyl)silyl]oxy]-3,3-dimethyl-2-hexanone		C₂₀H₄₄O₃Si₂	详情	详情
(XXIX)	40831	(7S,10R,11S,12S,16Z,19S)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one		C₄₅H₈₇NO₅SSi₃	详情	详情
(XXX)	40832	(7S,10R,11S,12S,16Z,19S)-7,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one		C₅₁H₁₀₁NO₅SSi₄	详情	详情
(XXXI)	40833	(5S,8R,9S,10S,14Z,17S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,10,14,19,19,20,20-tridecamethyl-17-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,18-dioxa-3,19-disila-14-henicosen-7-one		C₄₅H₈₇NO₅SSi₃	详情	详情
(XXXII)	40834	(3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid		C₄₅H₈₅NO₆SSi₃	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VI)

The ketonic intermediate (VI) has been obtained as follows: The condensation of the 3-(tert-butyldimethylsilyloxy)propionaldehyde (I) with the silylated enol ether (II), catalyzed by the chiral boron reagent (III), gives the phenyl hydroxyester (IV), which is protected with Tbdms-Cl to provide the silyl ether (V). Finally, the Grignard reaction of (V) with Et-MgBr affords the target ketonic intermediate (VI).

参考文献中间体

合成目标

【1】 Chen, Y.; Taylor, R.E.; Total synthesis of epothilones B and D. Org Lett 2001, 3, 14, 2221.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	45546	3-[[tert-butyl(dimethyl)silyl]oxy]propanal	570-24-1	C₉H₂₀O₂Si	详情	详情
(II)	52563	trimethyl{[2-methyl-1-(phenyloxy)-1-propenyl]oxy}silane; 2-methyl-1-(phenyloxy)-1-propenyl trimethylsilyl ether		C₁₃H₂₀O₂Si	详情	详情
(III)	52564	4-(1-methylethyl)-3-[(4-nitrophenyl)sulfonyl]-1,3,2-oxazaborolidin-5-one		C₁₁H₁₃BN₂O₆S	详情	详情
(IV)	52565	phenyl 5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-hydroxy-2,2-dimethylpentanoate		C₁₉H₃₂O₄Si	详情	详情
(V)	52566	phenyl 3,5-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2,2-dimethylpentanoate		C₂₅H₄₆O₄Si₂	详情	详情
(VI)	40830	(5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone		C₂₁H₄₆O₃Si₂	详情	详情

合成路线5

该中间体在本合成路线中的序号：(VI)

The allylation of 2-(2-methylthiazol-4-ylmethylene)propionaldehyde (X) with allyl(diisopinocampheyl)borane gives the chiral secondary alcohol (XI), which is protected with Tbdms-Cl, yielding the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and NaIO4 affords the chiral aldehyde (XIII), which is condensed with the intermediate iodovinyl compound (IX) by means of Ni/Cr to provide the allyl alcohol derivative (XIV). The reaction of (XIV) with SOCl2 gives the rearranged chloromethyl compound (XV), which is treated with LiEt3BH to cleave the oxazolidine chiral auxiliary and dechlorinate the chloromethyl group, yielding the primary alcohol (XVI). The controlled oxidation of the OH group of (XVI) with PCC affords the aldehyde (XVII), which is submitted to an aldol condensation with the intermediate ketone (VI) by means of LDA to provide the aldol (XVIII). The protection of the OH group of (XVIII) with Tbdms-Cl gives the fully silylated compound (XIX), which is regioselectively monodesilylated with camphorsulfonic acid (CSA) to yield the primary alcohol (XX).

参考文献中间体

合成目标

【1】 Chen, Y.; Taylor, R.E.; Total synthesis of epothilones B and D. Org Lett 2001, 3, 14, 2221.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	40830	(5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone	C₂₁H₄₆O₃Si₂	详情	详情
(IX)	52569	3-(6-iodo-2-methyl-6-heptenoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one	C₁₈H₂₂INO₃	详情	详情
(X)	44456	(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal	C₈H₉NOS	详情	详情
(XI)	43171	(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol	C₁₁H₁₅NOS	详情	详情
(XII)	44444	4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether	C₁₇H₂₉NOSSi	详情	详情
(XIII)	40822	(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal	C₁₆H₂₇NO₂SSi	详情	详情
(XIV)	52571	3-[9-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-2,10-dimethyl-6-methylidene-11-(2-methyl-1,3-thiazol-4-yl)-10-undecenoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one	C₃₄H₅₀N₂O₅SSi	详情	详情
(XV)	52570	3-[6-(chloromethyl)-9-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one	C₃₄H₄₉ClN₂O₄SSi	详情	详情
(XVI)	40828	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol	C₂₄H₄₃NO₂SSi	详情	详情
(XVII)	40829	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal	C₂₄H₄₁NO₂SSi	详情	详情
(XVIII)	40831	(7S,10R,11S,12S,16Z,19S)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one	C₄₅H₈₇NO₅SSi₃	详情	详情
(XIX)	40832	(7S,10R,11S,12S,16Z,19S)-7,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one	C₅₁H₁₀₁NO₅SSi₄	详情	详情
(XX)	40833	(5S,8R,9S,10S,14Z,17S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,10,14,19,19,20,20-tridecamethyl-17-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,18-dioxa-3,19-disila-14-henicosen-7-one	C₄₅H₈₇NO₅SSi₃	详情	详情

合成路线6

该中间体在本合成路线中的序号：(XXVII)

Assembly of the target compound: The enantioselective condensation of 3-(tert-butyldimethylsilyloxy)propanal (XX) with ketene acetal (XXI) catalyzed by N-tosyl-D-valine and BH3/THF gives the beta-hydroxyester (XXII), which is silylated with Tbdms-OTf, yielding the bis-silyl ether (XXIII). The reduction of (XXIII) with DIBAL in toluene affords the carbinol (XXIV), which is oxidized to the corresponding aldehyde (XXV) with DMP in dichloromethane. The Grignard condensation of (XXV) with Et-MgBr in ethyl ether gives the secondary alcohol (XXVI), which is oxidized with DMP as before to yield the ketone (XXVII). Alternatively, the silylated ester (XXIII) can be treated with Tms-CH2-Li in pentane/methanol to give the methyl ketone (XXVIII), which is methylated again with MeI and LDA in THF to afford the ketone (XXVII). The condensation of ketone (XXVII) with the intermediate carbaldehyde (XIX) by means of BuLi in THF gives the adduct (XXIX), which is silylated with Tbdms-OTf, yielding the fully silylated compound (XXX). The selective monodesilylation of (XXX) with CSA in MeOH/dichloromethane affords the primary alcohol (XXXI), which is oxidized with DMP and NaClO2 to provide the carboxylic acid (XXXII).

参考文献中间体

合成目标

【1】 Mulzer, J.; et al.; Total synthesis of epothilones B and D. J Org Chem 2000, 65, 22, 7456.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIX)	40829	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal		C₂₄H₄₁NO₂SSi	详情	详情
(XX)	45546	3-[[tert-butyl(dimethyl)silyl]oxy]propanal	570-24-1	C₉H₂₀O₂Si	详情	详情
(XXI)	42016	1-Methoxy-2-methyl-1-(trimethylsiloxy)propene;1-Methoxy-2,2-dimethyl-1-(trimethylsiloxy)ethene;1-Methoxy-1-(trimethylsilyloxy)-2-methylpropene;[(1-methoxy-2-methyl-1-propenyl)oxy](trimethyl)silane; 1-methoxy-2-methyl-1-propenyl trimethylsilyl ether ;dimethylketene methyl trimethylsilyl acetal	31469-15-5	C₈H₁₈O₂Si	详情	详情
(XXII)	40843	methyl (3S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-2,2-dimethylpentanoate		C₁₄H₃₀O₄Si	详情	详情
(XXIII)	40844	methyl (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethylpentanoate		C₂₀H₄₄O₄Si₂	详情	详情
(XXIV)	40845	(3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethyl-1-pentanol		C₁₉H₄₄O₃Si₂	详情	详情
(XXV)	40846	(3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethylpentanal		C₁₉H₄₂O₃Si₂	详情	详情
(XXVI)	40847	(5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanol		C₂₁H₄₈O₃Si₂	详情	详情
(XXVII)	40830	(5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone		C₂₁H₄₆O₃Si₂	详情	详情
(XXVIII)	46137	(4S)-4,6-bis[[tert-butyl(dimethyl)silyl]oxy]-3,3-dimethyl-2-hexanone		C₂₀H₄₄O₃Si₂	详情	详情
(XXIX)	40831	(7S,10R,11S,12S,16Z,19S)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one		C₄₅H₈₇NO₅SSi₃	详情	详情
(XXX)	40832	(7S,10R,11S,12S,16Z,19S)-7,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one		C₅₁H₁₀₁NO₅SSi₄	详情	详情
(XXXI)	40833	(5S,8R,9S,10S,14Z,17S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,10,14,19,19,20,20-tridecamethyl-17-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,18-dioxa-3,19-disila-14-henicosen-7-one		C₄₅H₈₇NO₅SSi₃	详情	详情
(XXXII)	40834	(3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid		C₄₅H₈₅NO₆SSi₃	详情	详情

合成路线7

该中间体在本合成路线中的序号：(VI)

参考文献中间体

合成目标

【1】 Chen, Y.; Taylor, R.E.; Total synthesis of epothilones B and D. Org Lett 2001, 3, 14, 2221.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	45546	3-[[tert-butyl(dimethyl)silyl]oxy]propanal	570-24-1	C₉H₂₀O₂Si	详情	详情
(II)	52563	trimethyl{[2-methyl-1-(phenyloxy)-1-propenyl]oxy}silane; 2-methyl-1-(phenyloxy)-1-propenyl trimethylsilyl ether		C₁₃H₂₀O₂Si	详情	详情
(III)	52564	4-(1-methylethyl)-3-[(4-nitrophenyl)sulfonyl]-1,3,2-oxazaborolidin-5-one		C₁₁H₁₃BN₂O₆S	详情	详情
(IV)	52565	phenyl 5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-hydroxy-2,2-dimethylpentanoate		C₁₉H₃₂O₄Si	详情	详情
(V)	52566	phenyl 3,5-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2,2-dimethylpentanoate		C₂₅H₄₆O₄Si₂	详情	详情
(VI)	40830	(5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone		C₂₁H₄₆O₃Si₂	详情	详情

合成路线8

该中间体在本合成路线中的序号：(VI)

参考文献中间体

合成目标

【1】 Chen, Y.; Taylor, R.E.; Total synthesis of epothilones B and D. Org Lett 2001, 3, 14, 2221.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	40830	(5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone	C₂₁H₄₆O₃Si₂	详情	详情
(IX)	52569	3-(6-iodo-2-methyl-6-heptenoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one	C₁₈H₂₂INO₃	详情	详情
(X)	44456	(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal	C₈H₉NOS	详情	详情
(XI)	43171	(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol	C₁₁H₁₅NOS	详情	详情
(XII)	44444	4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether	C₁₇H₂₉NOSSi	详情	详情
(XIII)	40822	(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal	C₁₆H₂₇NO₂SSi	详情	详情
(XIV)	52571	3-[9-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-2,10-dimethyl-6-methylidene-11-(2-methyl-1,3-thiazol-4-yl)-10-undecenoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one	C₃₄H₅₀N₂O₅SSi	详情	详情
(XV)	52570	3-[6-(chloromethyl)-9-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one	C₃₄H₄₉ClN₂O₄SSi	详情	详情
(XVI)	40828	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol	C₂₄H₄₃NO₂SSi	详情	详情
(XVII)	40829	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal	C₂₄H₄₁NO₂SSi	详情	详情
(XVIII)	40831	(7S,10R,11S,12S,16Z,19S)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one	C₄₅H₈₇NO₅SSi₃	详情	详情
(XIX)	40832	(7S,10R,11S,12S,16Z,19S)-7,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one	C₅₁H₁₀₁NO₅SSi₄	详情	详情
(XX)	40833	(5S,8R,9S,10S,14Z,17S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,10,14,19,19,20,20-tridecamethyl-17-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,18-dioxa-3,19-disila-14-henicosen-7-one	C₄₅H₈₇NO₅SSi₃	详情	详情

合成路线9

该中间体在本合成路线中的序号：(XIX)

The condensation of aldehyde (XVIII) with the chiral 3-heptanone derivative (XIX) by means of LDA in THF gives the heptadecadien-7-ol derivative (XX), which is silylated with Tbdms-OTf to yield the fully silylated compound (XXI). The selective desilylation of the primary OH group with HF and pyridine in THF affords the heptadecadien-1-ol derivative (XXII), which is submitted to a Swern oxidation followed by a treatment with NaClO2 to provide the carboxylic acid (XXIII). The selective desilylation of the 15-hydroxyl of (XXII) by means of TBAF in THF gives the hydroxyacid (XXIV), which is submitted to macrolactonization by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF to yield the macrolactone (XXV). The fully deprotection of (XXV) with HF and pyridine affords the hydroxymethyl macrolactone (XXVI), which is epoxidated with Ti(O-iPr)4, diethyl-L-tartrate and tBu-OOH to provide the epoxidated precursor (XXVII). Finally, this compound is treated with diethylaminosulfurtrifluoride (DAST) in dichloromethane to furnish the target fluorinated epothilone.

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; Total synthesis of 26-hydroxy-epothilone B and related analogs via a macrolactonization based strategy. Tetrahedron 1998, 54, 25, 7127.
【2】 He, Y.; Yang, Z.; Nicolaou, C.K.; Ninkovic, S.; Pastor, J.; Roschangar, F.; Sarabia, F.; Vallberg, H.; Vourloumis, D.; Winssinger, N.; King, N.P.; Finlay, M.R.V. (Novartis AG; Scripps Research Institute); Epothilone analogs. JP 2001504856; WO 9825929 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XVIII)	54776	(2S,6E,9S,10E)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienal	C₄₃H₅₅NO₃SSi	详情	详情
(XIX)	40830	(5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone	C₂₁H₄₆O₃Si₂	详情	详情
(XX)	54777	(7S,10R,11S,12S,16E,19S)-7-{[tert-butyl(dimethyl)silyl]oxy}-11-hydroxy-2,2,3,3,8,8,10,12,21,21,22,22-dodecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-16-[(trityloxy)methyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one	C₆₄H₁₀₁NO₆SSi₃	详情	详情
(XXI)	54778	(7S,10R,11S,12S,16E,19S)-7,11-bis{[tert-butyl(dimethyl)silyl]oxy}-2,2,3,3,8,8,10,12,21,21,22,22-dodecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-16-[(trityloxy)methyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one	C₇₀H₁₁₅NO₆SSi₄	详情	详情
(XXII)	54779	(5S,8R,9S,10S,14E,17S)-9-{[tert-butyl(dimethyl)silyl]oxy}-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,10,19,19,20,20-dodecamethyl-17-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-14-[(trityloxy)methyl]-4,18-dioxa-3,19-disila-14-henicosen-7-one	C₆₄H₁₀₁NO₆SSi₃	详情	详情
(XXIII)	54780	(3S,6R,7S,8S,12E,15S,16E)-3,7,15-tris{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12-[(trityloxy)methyl]-12,16-heptadecadienoic acid	C₆₄H₉₉NO₇SSi₃	详情	详情
(XXIV)	54781	(3S,6R,7S,8S,12E,15S,16E)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12-[(trityloxy)methyl]-12,16-heptadecadienoic acid	C₅₈H₈₅NO₇SSi₂	详情	详情
(XXV)	54782	(4S,7R,8S,9S,16S)-4,8-bis{[tert-butyl(dimethyl)silyl]oxy}-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-13-[(trityloxy)methyl]oxa-13-cyclohexadecene-2,6-dione	C₅₈H₈₃NO₆SSi₂	详情	详情
(XXVI)	54783	(4S,7R,8S,9S,16S)-4,8-dihydroxy-13-(hydroxymethyl)-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione	C₂₇H₄₁NO₆S	详情	详情
(XXVII)	54784	(1R,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-16-(hydroxymethyl)-8,8,10,12-tetramethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione	C₂₇H₄₁NO₇S	详情	详情

Extended Information